Calciphylaxis & Renal Graft Failure: A Case Report

Calciphylaxis-Associated Second Renal Graft Failure and
Patient Loss: a Case Report and Review of the Literature
Gamal Aabed,1Othman Al Furayh,1Ali Al-Lehbi,1Hadeel Al Mana,2
Abdulla Al Ghamedi,1Ahmed Helmy3
Abstract
Objectives: Calciphylaxis is a small vessel disease
that affects 1% to 4% of patients undergoing
dialysis. Only 21 cases of postrenal transplant
calciphylaxis have been reported, but none has
been associated with primary graft failure or has
occurred in a second graft. We present the first case
of second renal graft calciphylaxis leading to
primary graft failure and death.
Materials and Methods: We reviewed the 22 cases,
including ours, and assessed risk factors,
management, and mortality for these cases.
Results: The mean age was 34.2 ± 10.6 years, 11
patients were males (50%), and 13 (57.9%)
underwent a deceased-donor renal transplant. The
mean pretransplant dialysis period was 35.7 ± 39.3
months, 22 patients (100%) were on steroid
therapy, 8 (36.4%) had a rejection, 18 (81.8%)
underwent postcalciphylaxis parathyroidectomy,
and 11 patients died (50%). Acute graft rejection
and its management in the presence of high
parathormone and divalent ion levels may be
associated with postrenal transplant calciphylaxis.
Conclusions: If the high parathormone levels are
not adequately suppressed with medical treatment,
prerenal transplant preparation should include
parathyroidectomy. In addition, steroids and other
immunosuppressive medications should be tapered
quickly in calciphylaxis patients, especially if a
patient’s life is at risk.
Key words: Calciphylaxis, Parathyroidectomy, Renal
transplant
Calciphylaxis is a small vessel disease characterized
by intimal proliferation, endovascular fibrosis, and
mural calcification resulting in end-organ ischemia
and damage (1). Therefore, calciphylaxis is
considered as one of the recognized causes of
morbidity and mortality in hemodialysis patients (2).
The first animal model of calciphylaxis was
described by Selye in the early 1960s (3). Although
most body organs can be affected by calciphylaxis,
its most common manifestations are skin ulcers, acral
gangrene, intestinal ischemia, and aortic calcification
(4-6). Sudden fatal pulmonary calcification also has
been reported after renal transplant (7).
To our knowledge, a total of 21 cases of postrenal
transplant calciphylaxis have been published in 13
reports (7-19). However, none of the patients had
calciphylaxis after the second renal allograft or has
entertained the possibility of calciphylaxis as one of
the causes of primary graft failure. In this case report,
we present, for the first time, a patient who lost his
second renal allograft and subsequently died owing
to calciphylaxis. We also pooled and analyzed the
previously reported 21 cases, in addition to our case,
to draw better conclusions and assess the risk factors,
management, and outcomes of this uncommon
complication.
Case report:
A 33-year-old patient with end-stage renal disease of
an unknown origin had hemodialysis for 3 months
in 1988, followed by a commercial, living, nonrelated
renal transplant abroad, which failed after 3 years.
The histopathology of the first graft, unfortunately,
was not provided. He underwent hemodialysis for
another 10 years, until he had the second commercial
Copyright © Başkent University 2008
Printed in Turkey. All Rights Reserved.
From the Sections of 1Nephrology, and 3Gastroenterology, Department of Medicine; and the
2Department of Pathology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi
Arabia
Address reprint requests to: Dr. Ahmed Helmy, Section of Gastroenterology, Department of
Medicine, MBC: 46, King Faisal Specialist Hospital and Research Center, PO Box: 3354, Riyadh
11211, Saudi Arabia
Phone: [phone] Fax: [phone] E-mail: [e-mail]
Experimental and Clinical Transplantation (2008) 4: 287-293

renal transplant abroad in August 2002. Immediately
after surgery, the patient resumed hemodialysis
because of delayed graft function. He refused a
kidney biopsy and was given antirejection therapy
in the form of pulse methylprednisone,
antilymphocyte globulin, and daclizumab. The
transplanted kidney did not show improvement, and
the patient was discharged home on prednisone,
mycophenolate, and Rapamune.
Six weeks after the retransplant, the patient was
admitted to King Faisal Specialist Hospital &
Research Center in an anuric state, and was
maintained on hemodialysis. Doppler ultrasound
showed patent graft vessels with increased vascular
resistance. A renal scan showed good perfusion, but
with no excretion. A kidney biopsy showed findings
consistent with acute tubular necrosis, and the
patient was continued on the same medications. Two
days after presentation, he developed a painful
violaceous skin rash (Figure 1A) on the trunk and on
the medial side of both thighs. Skin biopsy showed
only hemorrhagic necrosis of the epidermis. A few
days later, the skin rash progressed to necrotic deep
ulcers (Figure 1B). The differential diagnoses were
panniculitis, vasculitis, and calciphylaxis.
Results of a laboratory work-up for vasculitis was
negative. Protein electrophoresis showed low serum
albumin and hypogammaglobulinemia. Immuno-
fixation did not show a monoclonal band. The
patient’s hemoglobin level was 78 g/L, hematocrit,
0.25%; parathyroid hormone (PTH), 1456 ng/L;
corrected serum calcium, 2.43 mmol/L; phosphate,
2.43 mmol/L; Mg++, 0.78 mmol/L; alkaline
phosphatase, 314 IU/L; urea, 19 mmol/L; serum
creatinine, 702 µmol/L; CO2, 24 mmol/L; albumin,
24 g/L; protein S, 1.33 IU/mL (normal range, 0.67-
1.19 IU/mL); protein C, 0.75 IU/mL (normal range,
0.5-1.24); C-reactive protein, 171 mg/L increased to
489 mg/L at the time of the second skin biopsy. An
ultrasound scan of the neck showed enlargement of
the 4 parathyroid glands (hyperplasia), and a
diagnosis of parathyroid adenomas was confirmed
by technetium scan. A second skin biopsy showed
extensive subepidermal vascular calcification in the
media with intimal fibrosis (Figure 2C) consistent
with a diagnosis of calciphylaxis.
Ten days after admission, a total para-
thyroidectomy was done with dissection of the
thymus. This led to normalization of the corrected
serum calcium, phosphate, and alkaline phosphatase
levels, and the parathyroid hormone level remained
less than 1.2 ng/L. One week later, the graft showed
no signs of improvement. Therefore, another kidney
biopsy was done, which showed areas of infarction,
Figure 1. (A) Early stages of calciphylactic skin lesions appear as violaceous macules in the back. (B) Late stages of calciphylactic skin lesions appear as
bilateral deep necrotic ulcers in the thighs.
Figure 2. (A) Calcification within the renal tubules and interstitium (H&E; ×200). (B) Renal biopsy in which the deposited calcium stains black within the renal
tubules and interstitium (Von Kossa’s stain; ×400).(C) Medial calcification and intimal fibrosis of a small subcutaneous artery (H&E; ×400).
AB
B CA
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Gamal Aabed et al / Experimental and Clinical Transplantation (2008) 4: 287-293

rejection (Banff grade 2), and severe intratubular,
vascular, and interstitial calcium crystal deposition
(Figures 2A and 2B). Pulsed methylprednisone
therapy was given and mycophenolic acid was
changed to tacrolimus. However, the patient
continued to be anuric. Therefore, a decision to
withdraw all immunosuppressive medications was
made and the patient’s corticosteroid therapy was
tapered gradually.
A wound culture showed multi–drug-resistant
organisms including Klebsiella pneumonia,Escherichia
coli, Gram-positive rods resembling Propionibacterium
species, Yeast, and Gram-negative rods. A blood
culture was positive for Klebsiella, which was also
multidrug resistant. The patient was then maintained
on regular hemodialysis, antibiotics, total parenteral
nutrition, growth hormone and wound care.
However, he continued to deteriorate, developed
intractable sepsis, and finally died.
Results of pooled cases
After a thorough PubMed search, from 1969 until
2005, 21 cases of postrenal transplant calciphylaxis
were reported in 13 references (7-19). Our case
therefore is the 22nd. We have presented the
demographic, renal, and immunologic characteristics
of these patients, in addition to the interventions
given, and mortality data in Tables 1a and 1b. Pooled
results of the whole 22 case are presented in Table 2.
Table 1a. Characteristics of patients at the time of calciphylaxis (demographic and renal).
N R (case) Age (year) Time post-tx Sex PTH (week) Dialysis period (month) Ca++ x P+++ Ca++ (mg/dL) P+++(mg/dL)
1 7 42 5M? 24 34.86 8.3 4.2
2 8 41 12 F? 13 23.94 11.4 2.1
3 9 (2) 20 44 F? 5.5 58.00 9.5-10.5 5.8
4 (7) 18 60 M? 4.5 8.5-10.5 Normal
5 (8) 30 40 M? 1 39.60 9.3-10.5 3.4 – 4.6
6 (9) 20 56 M? 7 82.80 9.6-11.1 8
7 (10) 48 156 F? 6 36.73 10-12.6 2.5-4
8 10 (1) 20 104 F 935 pg/mL** 12 37.98 10.1-11 3.0-4.2
9 (2) 30 130 M 965 pg/mL** 43 33.02 9.1-9.5 3.0-4.1
10 (3) 28 228 M 130 pg/mL 24 11-13 ?
11 (4) 42 104 F 40 pg/mL* 36 42.42 10.1 4.2
12 11 42 20 F 1200 µL Eq/mL 15 23.00 9-11 2.3
13 12 (1) 50 8F1055 ng/mL†60 46.42 2.68‡1.25‡
14 (2) 30 72 M 793 ng/L†72 58.80 2.5‡1.9‡
15 13 30 3F? 84 High High
16 14 26 572 M 268 ng/L ? 87.36 9.1 9.6
17 15 43 1092 M 9.1 ng/mL§22 22.50 9 2.5
18 16 49 104 F 2.4 pmol/L 24 28.34 1.99‡1.15‡
19 17 50 52 M 6 pmol/L¶144 39.57 2.35‡1.36‡
20 18 25 28 F High 12 2.7‡Normal
21 19 (2) 36 20 F? 20 32.55 10.5 3.1
22 Our 33 4M1456 ng/L 120 73.09 2.43‡2.43‡
R, reference. ( ), case number in the reference. M, male. F, female. PTH, parathyroid hormone. ?, unknown. *The normal range in this case was 2-10 µL Eq/mL.
**The normal range was 75-675 pg/mL. §this level was 3 years before calciphylaxis. †the normal range was 10-55 ng/L. ¶the normal range in this case was 1-
5.5 pmol/L. ‡the unit is mmol/L. C++, calcium. P+++, phosphorus.
Table 1b. Further patients characteristics (transplant, intervention, and
mortality).
N R Tx Type PTx Rejection DGF On steroid Prednisone Died
(case) dosage (mg)
17 DD No Yes Yes Yes ? Yes
2 8 LR Yes No No Yes 30 No
39(2) LR Yes Yes ? Yes ? No
4 (7) LR Yes Yes No Yes ? No
5 (8) LR Yes ?? Yes 15 No
6 (9) LR Yes ?? Yes ? Yes
7 (10) DD Yes No No Yes 20 No
8 10 (1) LR Yes Yes Yes Yes 10 Yes
9 (2) DD Yes ?? Yes 15-20 Yes
10 (3) LR Yes Yes No Yes 12.5 Yes
11 (4) DD Yes No No Yes 4* No
12 11 DD Yes No No Yes 30 No
13 12 (1) DD Yes No No Yes 4* No
14 (2) DD Yes Yes No Yes 10* No
15 13 ? No ?? Yes ? Yes
16 14 LR No ?? Yes 10 No
17 15 DD Yes** Yes ? Yes ? Yes
18 16 DD No ?? Yes 24* No
19 17 DD Yes No No Yes 8 Yes
20 18 DD Yes No Yes Yes 7.5 Yes
21 19 (2) DD Yes No No Yes 20 Yes
22 Our DD Yes Yes Yes Yes 17.5 Yes
Abbreviations: R, reference; Tx, transplant; PTx, Parathyroidectomy; DGF,
delayed graft function; ?, unknown; DD, deceased donor; LR, Living-
related; *, methylprednisone; **, PTx was subtotal and was done 3 months
post-Tx and not as a treatment of calciphylaxis.
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Briefly, the mean ± SD age at presentation was 34.2 ±
10.6 years, there were 11 males (50%), and 13 (57.9%)
underwent deceased-donor renal transplant. The
mean ± SD pretransplant dialysis period was 35.7 ±
39.3 months, 22 patients were on steroid therapy, 8
had rejection (36.4%). Calciphylaxis developed after
a mean ± SD interval of 132.5 ± 246.8 week postrenal
transplant. In 18 patients (81.8%), total
parathyroidectomy was performed after the
occurrence of calciphylaxis, and mortality was
reported in 11 patients (50%) (Table 2).
Discussion
Calciphylaxis is a syndrome that affects between 1%
and 4% of all patients undergoing dialysis (20); it
leads to vasculopathy (in the form of widespread
calcification of blood vessels) with subsequent vessel
narrowing and tissue ischemia. Although Virchow
was the first to describe soft-tissue calcification
associated with renal failure (21), Selye, in early
1960s, produced data from experiments on rats that
showed that corticosteroid administration hastens
the development of calciphylaxis, especially when
given with calcium and parathyroid hormone (22).
Selye postulated “2 steps” for the calciphylaxis to
occur. The first is systemic sensitization induced by
agents such as parathyroid hormone, vitamin D,
phosphates, or calcium salts. The second step, which
comes after a period called the critical period, is the
exposure of the animal to challenging agents
resulting in extensive tissue calcification. These
"challengers" include glucocorticoids, egg albumin,
iron salt, and local trauma. This hypothesis of a
hypersensitivity phenomenon was further supported
in other animal studies (23, 24).
A case control study by Mazhar and associates,
showed that female sex, hyperphosphatemia, high
alkaline phosphatase, and low serum albumin are
risk factors for calciphylaxis and mortality in patients
with end-stage renal disease (1). Low serum albumin
as a risk factor for development of calciphylaxis also
was observed by Bleyer and associates, who noticed
a 17-fold increase in the risk of developing
calciphylaxis with each 1 g/L decrease in serum
albumin (25). This observation was supported by
Coats and associates, who reported a loss of more
than 10% body weight over 6 months preceding the
diagnosis of calciphylaxis in 7 out of 16 patients in
their series (26). Our patient had low serum albumin
at presentation (24 g/L), which dropped further to
18 g/L throughout the course of his illness.
Calciphylaxis may be precipitated by an
intravenous injection of iron (27-29) or calcium (7, 8,
12) before or after transplant. Analysis of the pooled
22 reported cases revealed that 3 of the 22 patients
(13.4%) had an intravenous calcium injection (7, 8,
12). The effect of glucocorticoids on the pathogenesis
of calciphylaxis is still not clear (3).
In some circumstances, glucocorticoids can
prevent calciphylaxis, while in others, it may
aggravate the disease process. Fader and Kang
reported calciphylaxis in a patient with advanced
liver disease treated with prednisone and albumin
infusion (30). Indeed, in an in vitro study by Mori
and associates (31), dexamethasone was found to
stimulate a cyclic adenosine monophosphate
response to parathyroid hormone, and to produce a
dose-dependent enhancement of vascular calcification.
Our patient, because of the delayed graft function and
rejection, was pulsed twice with high-dose
methylprednisone. This high corticosteroid dose was
Table 2. Pooled characteristics of postrenal transplant patients at the time
of calciphylaxis (n=22).
Variable Mean ± SD or n (%)
Age (years) 34.2 ± 10.6
Sex
M 11 (50.0)
F 11 (50.0)
Dialysis period (months) 35.7 ± 39.3
Transplant type
Deceased-donor 13 (57.9)
LR 8 (36.8)
Unknown 1 (5.3)
Time post-Tx (weeks)* 132.5 ± 246.8
Serum calcium (mg/dL) 10 ± 1.0
Phosphorus (mg/dL) 4.5 ± 2.1
Calcium phosphorus product 44.5 ± 19.8
DGF
Yes 8 (36.4)
No 8 (36.4)
Unknown 6 (27.3)
Previous rejection
Yes 8 (36.4)
No 8 (36.4)
Unknown 6 (27.3)
On steroid 22 (100.0)
Steroid dose (mg/day) ** 16 ± 8.0
Parathyroidectomy
Yes 18 (81.8)
No 4 (18.2)
Mortality 11 (50.0)
Abbreviations: DGF, delayed graft function; LR, Living-related; M, male;
F, female; *the median is 54 and the range is 1089 weeks; **after conversion
to predinsone; n, number; SD, standard deviation
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291
given in the presence of a very high level of
parathyroid hormone. Analysis of the 22 postrenal
transplant calciphylaxis patients showed that 100%
of the patients were on corticosteroid therapy (Table
2), some of them developed the calciphylaxis
immediately after treatment of rejection with pulse
steroids (7).
Only 4 cases of postrenal transplant calciphylaxis
reported histopathological findings of the allograft,
and there results were variable (7, 12, 13). In the case
reported by Giacobetti and associates, the graft
biopsy showed acute tubular necrosis (7), exactly like
the first biopsy obtained in our patient. This may
reflect early graft ischemia as a result of calciphylaxis
rather than as acute tubular necrosis that is
commonly seen in early postrenal transplant.
However, there was no histopathological follow-up
report of this patient, whose graft was removed on
the 45th day after transplant. The 2 cases reported by
Wenzel-Seifert and associates, showed calcified
microcylinders in the tubules of a transplanted
kidney, and chronic rejection with severe calcinosis
of the interstitium in a removed kidney (12). The
third was an autopsy of the allograft removed 3
weeks after renal transplant, which showed focal
calcification of the transplanted kidney (13). The
fourth showed intrarenal arteries with myointimal
calcification (13). In our patient, the calcification was
in the renal tubules and in the interstitium (Figures
2A and 2B).
Patients with calciphylaxis have an 8-fold
increased risk of death compared with controls (1).
The most common cause of death is infection (32), as
occurred with our patient. Indeed, the mortality was
reported in 11 of the 22 (50%) reported postrenal
transplant calciphylaxis patients (Tables 1b and 2).
This high rate of mortality emphasizes the
importance of prevention, early detection, and
treatment of such cases. Five patients (45.4%) had
acute rejection and were treated with pulse steroids,
and only 3 of the 11 deceased patients (27.3%) had no
history of acute rejection, while the rejection status
in the remaining 3 patients (27.3%) was unknown.
On the other hand, only 3 of the 11 patients (27.3%)
who survived had an acute rejection episode. This
may suggest the importance of acute rejection as risk
factor for calciphylaxis in the appropriate setting.
Eight of the 22 patients (36.4%) had pulse steroid
treatments at least once, and in 2 patients, the dosage
of oral steroid was increased significantly, just before
the diagnosis of calciphylaxis (8, 16). The underlying
risk factor among the majority of the patients is the
treatment with corticosteroid and an immuno-
suppressant.
The classic therapy of calciphylaxis involves
control of hyperphosphatemia, reduction of calcium
phosphorus product to < 55 mg/L, and total
parathyroidectomy (2). However, management of
postrenal transplant calciphylaxis patients remains a
matter of controversy. Subtotal total para-
thyroidectomy was required only in few cases of
persistent postrenal transplant hypercalcemia (33-
35). Geis and associates, suggested that
posttransplant total parathyroidectomy may
improve renal function, especially in patients with
high ionized calcium levels and progressive
deterioration of renal function (36). Similarly, Perloff
and associates, recommend performing a total
parathyroidectomy within 1 year of transplant, if
parathyroid hormone and serum calcium levels are
persistently elevated (10).
Fox and associates, reported healing of the skin
lesions after total parathyroidectomy (11). As a
consequence, they suggested performing total
parathyroidectomy for patients with a functioning
graft, and withdrawal of the immunosuppressive
agents in patients with nonfunctioning grafts.
Revision of the 22 postrenal transplant calciphylaxis
patients, all of the patients (100%) who showed
improvement had a total parathyroidectomy, while
9 of the 11 patients (81.8%) who died had a total
parathyroidectomy. This is similar to what was
reported in patients without a renal transplant. Chan
and associates, reviewed 47 calciphylaxis cases, and
noted that the survival rate of patients who
underwent a total parathyroidectomy was similar to
those who did not (37). This also is supported by the
study of Budisavijevic and associates, in which 50%
of the 31 patients who had a total parathyroidectomy
performed after calciphylaxis died within 9 weeks of
the total parathyroidectomy (38). Thus, the
importance of a total parathyroidectomy in the
management of postrenal transplant calciphylaxis
needs further evaluation. In our patient, a total
parathyroidectomy did not stop the progression of
the skin ulcers. This may be explained by the
continuous challenging effect of corticosteroid given
as pulse therapy for rejection. When corticosteroids
were discontinued in some patients after graft failure
the wounds healed, and the patients were saved (9).
Gamal Aabed et al / Experimental and Clinical Transplantation (2008) 4: 287-293